The brain's opioid system plays an important role in reward mechanisms and recently it has been targeted in treatment efforts using the opiate antagonist, naltrexone. Our recent findings provide strong evidence for dampened CNS opioid activity in the offspring of alcoholics, an abnormality predating heavy alcohol drinking. However, we know little about the underlying differences in the endogenous opioid system between healthy individuals and the alcohol dependent population. Indeed, little human data exists which address the question ofwhether there are abnormalities in the opioid system in alcohol dependent, individuals and whether such differences are a consequence of genetic determinants, or a consequence of heavy alcohol use or a combination of both. The lack of knowledge of the role of endogenous opioids in alcoholism lias been due primarily to difficulties in making measurements in human subjccis. However, the hypothalamic-pituitary-adrenal (HPA) axis can provide useful measurements of endogenous opioid activity. This is because the HPA axis is modulated by hypothalamic opioid activity. Induction of opioid receptor blockade stimulates the HPA axis allowing a noninvasive, functional assessment of the hypothalamic opioid system . We propose to utilize this neuroendocrine strategy to measure opioid activity in alcohol dependent persons at various stages of their disorder. In Specific Aim 1, we will measure opioid activity in alcohol dependent individuals in early abstinencemonitored on the CRC and compare to controls. We will determine each subject's sensitivity to naloxone by venerating a dose response curve and then calculating the dose of naloxone required to induce a half-maxima!hormone response (ED50). We will relate this measurement of opioid activityto behavioral and physiologicalmeasures such as alcohol craving, mood and alcohol withdrawal symptoms.Alcoholics and controls will be equally representedby fami.y history positive (FHP) and family history negative (FHN) subjects. In Specific Aim II , we will measurethe change in ED50 values during eight weeks of supervised abstinenceon the CRC in alcohol dependent subjects compared to the control group. In Specific Aim 3 we will determine if naloxone sensitivity (ED50) measurementsobtained during controlled abstinence on the CRC predicts the time to relapse after discharge. This study will provide information on the activity of the endogenous opioid system as a function of alcoholism and as a function of family history of alcoholism. These findings will impact our understanding of the neurochemical factors that predispose to- and maintain heavy alcohol drinking. PERFORMANCE S\TE($) (organization, city, state} The Johns Hopkins University School of Medicine Baltimore, Maryland KEY PERSONNEL. See inslaiclions on Page 11. Usecontinuation pagesasnccdsd\o provide the required informal; Dn inthe format shown below. Name Organization Role on Project Gary Wand, M. D. Mary McCaul, Ph. D. Mark Peyrot, Ph D. Deborah Mangold The Johns Hopkins University Principal Investigator The Johns Hopkins University Co-Investigator Loyola College Statistician, n t Consultant, & Co-Investigator The Johns Hopkins University Post Doctoral Fellow PHS 398(Rev. 5/95) Page2 BB Number pages consecutively at the bottom throughout the application. Do not usesuffixes suchas 3a, 3b. Document 1 CC Prj^A| Investigator/ProgramDirector (Last, first,middle):. Typethe nameofthe principalinvestigator/programdireclorat thetopofeachprinted pageandeachcontinuation page.(Fortype specifications, see instructions onpage 6.) RESEARCH GRANT TABLE OF CONTENTS PageNumbers Face Page 1 Description,